This study is directed towards testing the hypothesis that specific immunoglobulin variable, diversity and joining gene segments are involved in human systemic lupus erythematosus and other autoimmune diseases. It utilizes a novel mouse model of disease which includes human variable, diversity, joining and constant region genes in transgenic mice which have been backcrossed into autoimmune strains. Additionally, experiments are described to utilize homologous recombination (knockout) strains so that we can develop murine strains containing exclusively human antibody genes. The development of disease in such mice will provide the opportunity to analyze the utilization of specific variable, diversity and joining gene segments in these important models of human autoimmune disease. In addition to providing important information concerning the development of the human antibody repertoire, these studies may provide important insights into the role of circulating antibody in human systemic lupus erythematosus and hemolytic anemia.